tbuckley/cabot-search huggingface dataset:
Nanogel-mediated delivery of oncomodulin secreted from regeneration-associated macrophages promotes sensory axon regeneration in the spinal cord
Authors: Min Jung Kwon, Yeojin Seo, Hana Cho, Hyung Soon Kim, Young Joo Oh, Simay Genişcan, Minjae Kim, Hee Hwan Park, Eun-Hye Joe, Myung-Hee Kwon, Han Chang Kang, Byung Gon Kim
Journal: Theranostics (2022)

Preconditioning nerve injury enhances axonal regeneration of dorsal root ganglia (DRG) neurons in part by driving pro-regenerative perineuronal macrophage activation.How these macrophages influence the neuronal capacity of axon regeneration remains elusive.We report that oncomodulin (ONCM) is produced from the regeneration-associated macrophages and strongly influences regeneration of DRG sensory axons.We also attempted to promote sensory axon regeneration by nanogel-mediated delivery of ONCM to DRGs.Methods: In vitro neuron-macrophage interaction model and preconditioning sciatic nerve injury were used to verify the necessity of ONCM in preconditioning injury-induced neurite outgrowth.We developed a nanogel-mediated delivery system in which electrostatic encapsulation of ONCM by a reducible epsilon-poly(L-lysine)-nanogel (REPL-NG) enabled a controlled release of ONCM.Results: Sciatic nerve injury upregulated ONCM in DRG macrophages.ONCM in macrophages was necessary to produce pro-regenerative macrophages in the in vitro model of neuron-macrophage interaction and played an essential role in preconditioning-induced neurite outgrowth.ONCM increased neurite outgrowth in cultured DRG neurons by activating a distinct gene set, particularly neuropeptide-related genes.Increasing extracellularly secreted ONCM in DRGs sufficiently enhanced the capacity of neurite outgrowth.Intraganglionic injection of REPL-NG/ONCM complex allowed sustained ONCM activity in DRG tissue and achieved a remarkable long-range regeneration of dorsal column sensory axons beyond spinal cord lesion.Conclusion: NG-mediated ONCM delivery could be exploited as a therapeutic strategy for promoting sensory axon regeneration following spinal cord injury.
Single-cell transcriptomics reveals the regulative roles of cancer associated fibroblasts in tumor immune microenvironment of recurrent osteosarcoma
Authors: Xin Huang, Lutong Wang, Haoyu Guo, Weiyue Zhang, Zengwu Shao
Journal: Theranostics (2022)

Rationale: Osteosarcoma (OS) is the most common primary bone tumor with a poor prognosis, but the detailed mechanism is still unclear.A comprehensive investigation of tumor microenvironment (TME) of OS might help find effective anti-tumor strategies.Single-cell transcriptomics is a powerful new tool to explore TME.Therefore, this study is designed to investigate the TME and gene expression pattern of primary and recurrent OS at the single-cell level.Methods: The single-cell RNA sequencing and bioinformatic analysis were conducted to investigate the cellular constitution of primary, recurrent, and lung metastatic OS lesions according to the datasets of GSE152048 and GSE162454.TIMER database was used to investigate the role of LOX in the prognosis of sarcoma.The functions of related cells and markers were further confirmed by in vitro and in vivo experiments.Results: Cancer associated fibroblasts (CAFs) were found with a higher infiltrating level in recurrent OS, and were enriched in the epithelial-mesenchymal transition (EMT) pathway.CAFs showed remarkably increased expression of LOX, which might lead to EMT and poor prognosis of OS.Mechanically, LOX regulated the function of CAFs and macrophage polarization to remodel the tumor immune microenvironment.Moreover, LOX inhibitor could inhibit migration and promote apoptosis of OS both in vitro and in vivo.Conclusions: This study revealed the heterogeneity of recurrent OS and highlighted an innovative mechanism that CAFs regulate EMT of OS via LOX.Targeting LOX of CAFs showed promising efficacy in remodeling TME and treating recurrent OS.
Emerging nanozyme-based multimodal synergistic therapies in combating bacterial infections
Authors: Yanmei Zhang, Xin Hu, Jing Shang, Wenhui Shao, Liming Jin, Chunshan Quan, Jun Li
Journal: Theranostics (2022)

Pathogenic infections have emerged as major threats to global public health. Multidrug resistance induced by the abuse of antibiotics makes the anti-infection therapies to be a global challenge. Thus, it is urgent to develop novel, efficient and biosafe antibiotic alternatives for future antibacterial therapy. Recently, nanozymes have emerged as promising antibiotic alternatives for combating bacterial infections. More significantly, the multimodal synergistic nanozyme-based antibacterial systems open novel disinfection pathways. In this review, we are mainly focusing on the recent research progress of nanozyme-based multimodal synergistic therapies to eliminate bacterial infections. Their antibacterial mechanism, the synergistic antibacterial systems are systematically summarized and discussed according to the combination of mechanisms and the purpose to improve their antibacterial efficiency, biosafety and specificity. Finanly, the current challenges and prospects of the multimodal synergistic antibacterial systems are proposed.
President's Pick for NCI: Monica Bertagnolli, MD
Journal: Cancer Discovery (2022)

President Joe Biden has chosen Monica Bertagnolli, MD, a renowned surgical oncologist, group chair of the Alliance for Clinical Trials in Oncology, and former president of the American Society of Clinical Oncology, to be the 16th director of the NCI. She will be the first woman to hold the position since the agency's founding in 1937. The news was greeted with excitement and praise from cancer researchers and clinicians.
SARS-CoV-2 infection in households with and without young children: Nationwide cohort study, Denmark, 27 February 2020 to 26 February 2021
Authors: Anders Husby, Giulia Corn, Tyra Grove Krause
Journal: Eurosurveillance (2022)

Background Infections with seasonally spreading coronaviruses are common among young children during winter months in the northern hemisphere; the immunological response lasts around a year. However, it is not clear if living with young children changes the risk of SARS-CoV-2 infection among adults. Aim Our aim was to investigate the association between living in a household with younger children and the risk of SARS-CoV-2 infections and hospitalisation. Methods In a nationwide cohort study, we followed all adults in Denmark aged 18 to 60 years from 27 February 2020 to 26 February 2021. Hazard ratios of SARS-CoV-2 infection by number of 10 months to 5 year-old children in the household were estimated using Cox regression adjusted for adult age, sex and other potential confounders. In a sensitivity analysis, we investigated the effect of the children's age. Results Among 450,007 adults living in households with young children, 19,555 were tested positive for SARS-CoV-2, while among 2,628,500 adults without young children in their household, 110,069 were tested positive for SARS-CoV-2 (adjusted hazard ratio (aHR) = 1.10; 95% confidence interval (CI): 1.08–1.12). Among adults with young children, 620 were hospitalised with SARS-CoV-2, while 4,002 adults without children were hospitalised with SARS-CoV-2 (aHR = 0.97; 95% CI: 0.88–1.08). Sensitivity analyses found that an increasing number of younger children substantially increased the risk of SARS-CoV-2 infection but not hospitalisation. Conclusion Living in a household with young children was associated with a small increased risk of SARS-CoV-2 infection.
Letter to the editor: HCC EV ECG score: An extracellular vesicle–based protein assay for detection of early‐stage HCC
Authors: Wenhao Luo, Yu Gu, Taiping Zhang
Journal: Hepatology (2022)

To the editor, We read the study by Sun et al., in which the HCC extracellular vesicles (EV) electrocardiogram (ECG) score demonstrated great potential for detecting early‐stage HCC.1 However, we have some concerns about this conclusion. First, in this study, we have noticed that the HCC EV ECG score is based on the comparison of patients with early‐stage HCC and liver cirrhosis, with an impressive performance of sensitivity and specificity. However, the benefit of the HCC EV ECG score would be limited, because only patients with early‐stage HCC and liver cirrhosis were included. We suggested a more appropriate comparison of early‐stage HCC and samples from a healthy population. Moreover, the cancer types and sample of the control group are too few. A recent study showed that there is a close relationship between CD147+EVs and other cancer types such as colorectal cancer and renal cell carcinoma.2,3 However, no patients with colorectal or renal cancer were included in this study, which is susceptible to selection bias. Second, in figure S14 of this study, HCC EV ECG scores from both patients with early‐stage HCC and advanced‐stage HCC were significantly higher than patients with other cancers, which deteriorates the specificity of HCC EV ECG for detecting the early stage of HCC. Third, this study aimed to discover biomarkers for early detection of HCC. However, this study used the ECG score, including three HCC EV surface protein signatures to distinguish early‐stage HCC from cirrhosis, which increases the sensitivity compared with one EV surface protein signature. Moreover, a previous study has also identified some EV markers like mothers against decapentaplegic homolog 3 (SMAD3) for early detection of HCC,4 but no statement about the SMAD3 was shown. Finally, a recent study demonstrated the significant role of cost‐effectiveness in early detection for HCC.5 In this study, detecting three HCC EVs to distinguish early‐stage HCC from cirrhosis enhances the unnecessary cost of patients for detection. In conclusion, whether the HCC EV ECG score is necessary to augment current surveillance methods and improve patients' outcomes remains controversial.
Publisher Correction: Reporting guideline for the early-stage clinical evaluation of decision support systems driven by artificial intelligence: DECIDE-AI
Authors: Baptiste Vasey, Myura Nagendran, Bruce Campbell, David A. Clifton, Gary S. Collins, Spiros Denaxas, Alastair K. Denniston, Livia Faes, Bart Geerts, Mudathir Ibrahim, Xiaoxuan Liu, Bilal A. Mateen, Piyush Mathur, Melissa D. McCradden, Lauren Morgan, Johan Ordish, Campbell Rogers, Suchi Saria, Daniel S. W. Ting, Peter Watkinson, Wim Weber, Peter Wheatstone, Peter McCulloch, Aaron Y. Lee, Alan G. Fraser, Ali Connell, Alykhan Vira, Andre Esteva, Andrew D. Althouse, Andrew L. Beam, Anne de Hond, Anne-Laure Boulesteix, Anthony Bradlow, Ari Ercole, Arsenio Paez, Athanasios Tsanas, Barry Kirby, Ben Glocker, Carmelo Velardo, Chang Min Park, Charisma Hehakaya, Chris Baber, Chris Paton, Christian Johner, Christopher J. Kelly, Christopher J. Vincent, Christopher Yau, Clare McGenity, Constantine Gatsonis, Corinne Faivre-Finn, Crispin Simon, Danielle Sent, Danilo Bzdok, Darren Treanor, David C. Wong, David F. Steiner, David Higgins, Dawn Benson, Declan P. O’Regan, Dinesh V. Gunasekaran, Dominic Danks, Emanuele Neri, Evangelia Kyrimi, Falk Schwendicke, Farah Magrabi, Frances Ives, Frank E. Rademakers, George E. Fowler, Giuseppe Frau, H. D. Jeffry Hogg, Hani J. Marcus, Heang-Ping Chan, Henry Xiang, Hugh F. McIntyre, Hugh Harvey, Hyungjin Kim, Ibrahim Habli, James C. Fackler, James Shaw, Janet Higham, Jared M. Wohlgemut, Jaron Chong, Jean-Emmanuel Bibault, Jérémie F. Cohen, Jesper Kers, Jessica Morley, Joachim Krois, Joao Monteiro, Joel Horovitz, John Fletcher, Jonathan Taylor, Jung Hyun Yoon, Karandeep Singh, Karel G. M. Moons, Kassandra Karpathakis, Ken Catchpole, Kerenza Hood, Konstantinos Balaskas, Konstantinos Kamnitsas, Laura Militello, Laure Wynants, Lauren Oakden-Rayner, Laurence B. Lovat, Luc J. M. Smits, Ludwig C. Hinske, M. Khair ElZarrad, Maarten van Smeden, Mara Giavina-Bianchi, Mark Daley, Mark P. Sendak, Mark Sujan, Maroeska Rovers, Matthew DeCamp, Matthew Woodward, Matthieu Komorowski, Max Marsden, Maxine Mackintosh, Michael D. Abramoff, Miguel Ángel Armengol de la Hoz, Neale Hambidge, Neil Daly, Niels Peek, Oliver Redfern, Omer F. Ahmad, Patrick M. Bossuyt, Pearse A. Keane, Pedro N. P. Ferreira, Petra Schnell-Inderst, Pietro Mascagni, Prokar Dasgupta, Pujun Guan, Rachel Barnett, Rawen Kader, Reena Chopra, Ritse M. Mann, Rupa Sarkar, Saana M. Mäenpää, Samuel G. Finlayson, Sarah Vollam, Sebastian J. Vollmer, Seong Ho Park, Shakir Laher, Shalmali Joshi, Siri L. van der Meijden, Susan C. Shelmerdine, Tien-En Tan, Tom J. W. Stocker, Valentina Giannini, Vince I. Madai, Virginia Newcombe, Wei Yan Ng, Wendy A. Rogers, William Ogallo, Yoonyoung Park, Zane B. Perkins
Journal: Nature Medicine (2022)
Ischemia-Selective Cardioprotection by Malonate for Ischemia/Reperfusion Injury
Authors: Hiran A. Prag, Dunja Aksentijevic, Andreas Dannhorn, Abigail V. Giles, John F. Mulvey, Olga Sauchanka, Luping Du, Georgina Bates, Johannes Reinhold, Duvaraka Kula-Alwar, Zhelong Xu, Luc Pellerin, Richard J. A. Goodwin, Michael P. Murphy, Thomas Krieg
Journal: Circulation Research (2022)

Background: Inhibiting SDH (succinate dehydrogenase), with the competitive inhibitor malonate, has shown promise in ameliorating ischemia/reperfusion injury. However, key for translation to the clinic is understanding the mechanism of malonate entry into cells to enable inhibition of SDH, its mitochondrial target, as malonate itself poorly permeates cellular membranes. The possibility of malonate selectively entering the at-risk heart tissue on reperfusion, however, remains unexplored. Methods: C57BL/6J mice, C2C12 and H9c2 myoblasts, and HeLa cells were used to elucidate the mechanism of selective malonate uptake into the ischemic heart upon reperfusion. Cells were treated with malonate while varying pH or together with transport inhibitors. Mouse hearts were either perfused ex vivo (Langendorff) or subjected to in vivo left anterior descending coronary artery ligation as models of ischemia/reperfusion injury. Succinate and malonate levels were assessed by liquid chromatography-tandem mass spectrometry LC-MS/MS, in vivo by mass spectrometry imaging, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining. Results: Malonate was robustly protective against cardiac ischemia/reperfusion injury, but only if administered at reperfusion and not when infused before ischemia. The extent of malonate uptake into the heart was proportional to the duration of ischemia. Malonate entry into cardiomyocytes in vivo and in vitro was dramatically increased at the low pH (≈6.5) associated with ischemia. This increased uptake of malonate was blocked by selective inhibition of MCT1 (monocarboxylate transporter 1). Reperfusion of the ischemic heart region with malonate led to selective SDH inhibition in the at-risk region. Acid-formulation greatly enhances the cardioprotective potency of malonate. Conclusions: Cardioprotection by malonate is dependent on its entry into cardiomyocytes. This is facilitated by the local decrease in pH that occurs during ischemia, leading to its selective uptake upon reperfusion into the at-risk tissue, via MCT1. Thus, malonate’s preferential uptake in reperfused tissue means it is an at-risk tissue-selective drug that protects against cardiac ischemia/reperfusion injury.
Origination of LTR Retroelement–Derived <i>NYNRIN</i> Coincides with Therian Placental Emergence
Authors: Arnon Plianchaisuk, Kazuya Kusama, Kiyoko Kato, Sira Sriswasdi, Kazuhiro Tamura, Wataru Iwasaki
Journal: Molecular Biology and Evolution (2022)

The emergence of the placenta is a revolutionary event in the evolution of therian mammals, to which some LTR retroelement-derived genes, such as PEG10, RTL1, and syncytin, are known to contribute. However, therian genomes contain many more LTR retroelement-derived genes that may also have contributed to placental evolution. We conducted large-scale evolutionary genomic and transcriptomic analyses to comprehensively search for LTR retroelement-derived genes whose origination coincided with therian placental emergence and that became consistently expressed in therian placentae. We identified NYNRIN as another Ty3/Gypsy LTR retroelement-derived gene likely to contribute to placental emergence in the therian stem lineage. NYNRIN knockdown inhibited the invasion of HTR8/SVneo invasive-type trophoblasts, whereas the knockdown of its nonretroelement-derived homolog KHNYN did not. Functional enrichment analyses suggested that NYNRIN modulates trophoblast invasion by regulating epithelial-mesenchymal transition and extracellular matrix remodeling and that the ubiquitin-proteasome system is responsible for the functional differences between NYNRIN and KHNYN. These findings extend our knowledge of the roles of LTR retroelement-derived genes in the evolution of therian mammals.
Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood–brain barrier (BBB) to manage neurological disorders
Authors: A.C. Correia, A.R. Monteiro, R. Silva, J.N. Moreira, J.M. Sousa Lobo, A.C. Silva
Journal: Advanced Drug Delivery Reviews (2022)
Hepatocellular carcinoma incidence is decreasing in Korea but increasing in the very elderly
Authors: Young Eun Chon, Seong Yong Park, Han Pyo Hong, Donghee Son, Jonghyun Lee, Eileen Yoon, Soon Sun Kim, Sang Bong Ahn, Soung Won Jeong, Dae Won Jun
Journal: Clinical and Molecular Hepatology (2022)

A comprehensive analysis of trends in the incidence of hepatocellular carcinoma (HCC) is important for planning public health initiatives. We aimed to analyze the trends in HCC incidence in South Korea over 10 years and to predict the incidence for the year 2028.
Peripheral Blood <scp>DNA</scp> Methylation–Based Machine Learning Models for Prediction of Knee Osteoarthritis Progression: Biologic Specimens and Data From the Osteoarthritis Initiative and Johnston County Osteoarthritis Project
Authors: Christopher M. Dunn, Cassandra Sturdy, Cassandra Velasco, Leoni Schlupp, Emmaline Prinz, Vladislav Izda, Liubov Arbeeva, Yvonne M. Golightly, Amanda E. Nelson, Matlock A. Jeffries
Journal: Arthritis & Rheumatology (2022)

The lack of accurate biomarkers to predict knee osteoarthritis (OA) progression is a key unmet need in OA clinical research. The objective of this study was to develop baseline peripheral blood epigenetic biomarker models to predict knee OA progression.
Cellular senescence in neuroinflammatory disease: new therapies for old cells?
Authors: Christopher Nelke, Christina B. Schroeter, Marc Pawlitzki, Sven G. Meuth, Tobias Ruck
Journal: Trends in Molecular Medicine (2022)

Neuroinflammatory diseases remain a therapeutic challenge, notably when progressing towards neurodegeneration. In this context, multiple sclerosis represents a central nervous system (CNS) disorder that combines pathogenic inflammatory and degenerative processes. Immunosuppression is effective for managing inflammatory activity, but neurodegenerative processes secondary to chronic inflammation are often refractory to contemporary treatments. Recent evidence indicates that pathways involved in chronic neuroinflammation demonstrate features of cellular senescence. These features could provide a framework that could serve as a target for senotherapeutics. In this review, we discuss the unmet need for strategies capable of overcoming the treatment resistance of neuroinflammatory diseases, and we discuss the potential of cellular senescence towards developing these strategies.
Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment
Authors: Soo-Jeung Park, Young S. Hahn
Journal: Clinical and Molecular Hepatology (2022)

Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
Multifunctional hydrogel enhances bone regeneration through sustained release of Stromal Cell-Derived Factor-1α and exosomes
Authors: Lang Chen, Chenyan Yu, Yuan Xiong, Kai Chen, Pei Liu, Adriana C. Panayi, Xiufeng Xiao, Qian Feng, Bobin Mi, Guohui Liu
Journal: Bioactive Materials (2022)

Fracture nonunion remains a great challenge for orthopedic surgeons. Fracture repair comprises of three phases, the inflammatory, repair and remodeling stage. Extensive advancements have been made in the field of bone repair, including development of strategies to balance the M1/M2 macrophage populations, and to improve osteogenesis and angiogenesis. However, such developments focused on only one or the latter two phases, while ignoring the inflammatory phase during which cell recruitment occurs. In this study, we combined Stromal Cell-Derived Factor-1α (SDF-1α) and M2 macrophage derived exosomes (M2D-Exos) with a hyaluronic acid (HA)-based hydrogel precursor solution to synthesize an injectable, self-healing, adhesive HA@SDF-1α/M2D-Exos hydrogel. The HA hydrogel demonstrated good biocompatibility and hemostatic ability, with the 4% HA hydrogels displaying great antibacterial activity against gram-negative E. coli and gram-positive S. aureus and Methicillin-resistant Staphylococcus aureus (MRSA). Synchronously and sustainably released SDF-1α and M2D-Exos from the HA@SDF-1α/M2D-Exos hydrogel enhanced proliferation and migration of human bone marrow mesenchymal stem cell (HMSCs) and Human Umbilical Vein Endothelial Cells (HUVECs), promoting osteogenesis and angiogenesis both in vivo and in vitro. Overall, the developed HA@ SDF-1α/M2D-Exos hydrogel was compatible with the natural healing process of fractures and provides a new modality for accelerating bone repair by coupling osteogenesis, angiogenesis, and resisting infection at all stages.
Correction: Olfactory swab sampling optimization for α-synuclein aggregate detection in patients with Parkinson’s disease
Authors: Matilde Bongianni, Mauro Catalan, Daniela Perra, Elena Fontana, Francesco Janes, Claudio Bertolotti, Luca Sacchetto, Stefano Capaldi, Matteo Tagliapietra, Paola Polverino, Valentina Tommasini, Giulia Bellavita, Elham Ataie Kachoie, Roberto Baruca, Andrea Bernardini, Mariarosaria Valente, Michele Fiorini, Erika Bronzato, Stefano Tamburin, Laura Bertolasi, Lorenzo Brozzetti, Maria Paola Cecchini, Gianluigi Gigli, Salvatore Monaco, Paolo Manganotti, Gianluigi Zanusso
Journal: Translational Neurodegeneration (2022)